This invention relates to a novel process for the preparation of egolinylthioures derivatives by exchange of the carbonyl oxygen of ergolinylthiourea derivatives with sulfur.
The preparation of ergolinylthiourea derivatives has long been known in the art. However, all of the known processes possess severe disadvantages, e.g., they require many synthesis steps and do not produce the desired compounds selectively and in acceptable yields.
For example, processes known heretofore utilize, for the preparation of ergoline thiourea derivatives, 8-aminoergolines which are difficult to obtain. For example, 8-amines of 9,10-didehydroergoline derivatives can be poduced only by way of the multistage Curtius decomposition, yielding an 8.alpha.,.beta.-stereoisomer mixture that must be separated with additional work effort, and also resulting in a loss of yield [A. Hofmann, Helv. 30:44 (1947)].
The 8-aminoergoline derivatives with a C.sub.9 -C.sub.10 single bond can likewise be prepared only by way of multistage synthesis steps, in poor yields (EP 48 695).
The thus-obtained 8-ergolinylamines have heretofore been reacted either with isothiocyanates or 1,1'-thiocarbonyldiimidazole in order to produce thiourea derivatives.
With the use of isothiocyanates, thiourea derivatives can be obtained in one reaction step. However, this method cannot be used to produce 1,1-dialkyl thioureas which are of particular value in pharmacology.
For the preparation of 1,1-dialkyl thiourea derivatives, 8-ergolinylamines are allowed to react with 1,1'-thiocarbonyldiimidazole and therafter the resultant reactive intermediate product is converted to the desired thiourea derivative with a primary or secondary amine. This preparation method necessitates the use of a highly poisonous, expensive and thus industrially objectionable thiophosgene reagent.